Synthesis and Pharmacological Evaluation of a New Class of Peroxisome Proliferator‐Activated Receptor Modulators.

Abstract

Receptor binding activityReceptor binding activity X 0280 Synthesis and Pharmacological Evaluation of a New Class of Peroxisome Proliferator-Activated Receptor Modulators. -Three different series of 5-substituted 2-benzoylaminobenzoic acids such as (I), (II), and (III) are synthesized as PPARα/ γ modulators by using the Mitsunobu reaction and Suzuki coupling. The 5-substituted BVT.142 analogues (I), (IIa), and (IIb) are dual PPARα/γ agonists showing significantly more activity than the original hit, while compounds (IIc) and (IId) are potent and highly selective PPARγ agonists. Diaryl ethers (III) show the highest binding affinities and are highly selective as well. The new class activates the PPARγ receptor through interaction with a novel binding site. -(THOR*, M.; et al.; Bioorg. Med. Chem. Lett. 12 (2002) 24, 3565-3567; Dep. Med. Chem., Biovitrum AB, S-751 37 Uppsala, Swed.; Eng.) -H. Hoennerscheid 12-220

Mapping Functional Group Free Energy Patterns at Protein Occluded Sites: Nuclear Receptors and G-Protein Coupled Receptors

“…For instance, GW409544 that binds into both the LBP1 and LBP2 (PDB: 1K74) has very good overlap with APOLAR FragMaps A1, A2, and A3 (Figure C), leading to a favorable LGFE that correlates with its high binding affinity compared to the partial agonist decanoic acid or the thiazolidinediones such as the rosiglitazone. On the other hand, poor correlations are noted for Cerco-A (Figure D) driven by a lack of APOLAR FragMaps in the hydrophobic cavity between L262 and F287, where the dibenzofurancaboxamide functional group of Cerco-A binds. This is caused by the loss of this hydrophobic cavity due to 1) the high flexibilities of the side chains of these residues through the simulations (SI Figure S5A) and 2) the conformation of the loop connecting helices H2 and H3 built using MODELLER (SI Text, Section S1).…”

Design and Synthesis of the First Generation of Dithiolane Thiazolidinedione- and Phenylacetic Acid-Based PPARγ Agonists

“…28 Recently, several 5-substituted 2-benzoylaminobenzoic acid (2-BABAs) PPARγ modulators have been reported to exert their effect without direct interaction with residues of the AF-2 helix. In fact, the X-ray crystal structures of these compounds with PPARγ have revealed a unique binding mode involving hydrogen bonding interactions with Ser342, 29,30 an amino acid residue occupying a different arm of the Y-shaped LBD.…”

The PPARΩPocket: Renewed Opportunities for Drug Development

“…Considering ligands of synthetic origin, the ligand BVT.13 [159,212] (Figure S2) was observed to bind to PPARγ in a 1 : 1 stoichiometry in the crystal phase, primarily interacting with H3 and not with H12 [12,114,159]. And while HDX-MS experiments did not indicate that BVT.13 treatment stabilized H12 significantly compared to apo-PPARγ [114], the transcriptional response to BVT.13 was 60-80% of that of rosiglitazone, in PPARγ reporter gene assays [114,159].…”

“…Finally, during the development of the Ω pocketbinding PPARγ ligand BVT.13 [159,212], described in Section 5.3, three additional ligands, BVT.762, BVT.763, and Compound 5d ( Figure S3), also displayed binding to PPARα (K i = 25 μM, 20 μM, and 19 μM, respectively) and induced transcription in a PPARα reporter gene assay 9 PPAR Research with EC 50 = 5 μM, 3.8 μM, and 2.5 μM, respectively [212]. Although no data is available on their binding modes in the PPARα LBP or their influence on PPARα PTMs, the binding of BVT.13 to the PPARγ Ω pocket suggests that these ligand structures may be of interest in the development of ligands for the PPARα Ω pocket.…”